Protein kinase C (calcium/phospholipid protein kinase; PKC) catalyses phosphorylation of the amino acids serene and threonine. PKC is a ubiquitous enzyme in body tissues and is thought to play an important role in neurotransmission, tumor promotion, and cellular proliferation.
Because PKC has wide-ranging physiologic functions, safe and effective modulators of this enzyme will have great therapeutic value. PKC modulators may be useful in treatment of various diseases including inflammatory diseases, proliferative diseases such as psoriasis and various malignancies, neurologic disorders, endocrine disorders, and hypertension.
Compounds that have been identified as PKC inhibitors generally are categorized into five classes. The first class of modulating compounds are lipids which are structurally similar to diacylglycerol. These compounds, however, are not useful as therapeutic agents because they either are excluded from intracellular spaces or are metabolized very rapidly. (May, W., et al., Biochemistry 23:5036, 1984).
The second class of PKC modulating compounds is exemplified by the isoquinoline sulfonamide H-7 and its analogs. (Hidaka, H., et al., Biochemistry 23:5036, 1984). Examples of compounds in this second class include 4-aminomethyl-1-[2,3-(di-n-decyloxy)n-propyl]-4-phenylpiperidine (Shoji, et al. Biochem. Biophys. Res. Commun. 234:590, 1985), several phenothiazine agents (Mori, T., et al. J. Biol. Chem. 255:8378, 1980; Schatzman, R., et al. Biochem. Biophys. Res. Commun. 98:669, 1981), tamoxifen (O'Brien, C., et al. Cancer Res. 45:2462, 1985), quercetin (Srivastava, A., Biochem. Biophys. Res. Commun. 131:1, 1985), amiloride (Besterman, J., et al. J. Biol. Chem. 260:1155, 1985), verapamil (Mori, T., et al. J. Biol. Chem. 255:8378, 1980), adriamycin (Wise, B., et al. J. Biol. Chem. 257:8489, 1982), polymyxin B (Mazzei, G., et al. Biochem. Biophys. Res. Commun. 109:1129, 1982), gangliosides (Kim, J., Neurosci. Res. 15:159, 1986), sangivamycin (Loomis, C. and Bell R., J. Biol. Chem. 263:1682, 1988), retinal (Patarroyo, Immunobiol. 170:305, 1985), and staurosporine (Tamoki, T., et al. Biochem. Biophys. Res. Commun. 135:397, 1986). The compounds in the second class are not specific PKC inhibitors and thus are not useful as therapeutic modulators of PKC activity.
The third class of PKC modulators are peptides thought to bind to the pseudosubstrate site that maintains the enzyme in its inactive form (House, C. and Kemp, B., Science 238:1726, 1987). Peptide inhibitors, however, are excluded from the cytoplasm and therefore are useless as therapeutic agents.
The fourth class of compounds known to modulate PKC are aminoacridines. (Hannum, Y. and Bell, R., J. Biol. Chem. 263:5124, 1988).
The fifth class of compounds that are known to modulate PKC include sphingosine and related sphingolipids. (Bell, R., et al. Cold Spr. Harbor Sym. Quant. Biol. 53:103, 1988). Since sphingosines are major components of biological membranes, and are major dietary components, it is very difficult to use them or their derivatives therapeutically, particularly to treat a systemic disease.
Therefore, despite many years of research there remains a need for safe and effective PKC modulators that are useful therapeutic agents.